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The hypothalamus in the mammalian brain is responsible for regulating functions associated with survival and reproduction representing a complex set of highly interconnected, yet anatomically and functionally distinct, sub-regions. It remains unclear what factors drive the spatial organization of sub-regions within the hypothalamus. One potential factor may be structural connectivity of the network that promotes efficient function with well-connected sub-regions placed closer together geometrically, i.e., the strongest axonal signal transferred through the shortest geometrical distance. To empirically test for such efficiency, we use hypothalamic data derived from the Allen Mouse Brain Connectivity Atlas, which provides a structural connectivity map of mouse brain regions derived from a series of viral tracing experiments. Using both cost function minimization and comparison with a weighted, sphere-packing ensemble, we demonstrate that the sum of the distances between hypothalamic sub-regions are not close to the minimum possible distance, consistent with prior whole brain studies. However, if such distances are weighted by the inverse of the magnitude of the connectivity, their sum is among the lowest possible values. Specifically, the hypothalamus appears within the top 94th percentile of neural efficiencies of randomly packed configurations and within one standard deviation of the median efficiency when packings are optimized for maximal neural efficiency. Our results, therefore, indicate that a combination of geometrical and topological constraints help govern the structure of the hypothalamus. [ABSTRACT FROM AUTHOR]

Abstract A diet of energy-dense food, characterized mainly as a high-fat diet, leads to a persistent excessive consumption defined as overeating. According to the National Institute of Health, more than 2 in 3 adults in the United States are overweight or obese, straining our healthcare system with epidemic proportions. Diets that include abstaining from high-fat foods, ironically, result in an increase in motivation and craving for said high-fat foods, defined as an incubation effect because the behavior aids in developing overeating. Previously, we have shown that modulation of neuromedin U receptor 2 (NMUR2) in the paraventricular nucleus of the hypothalamus (PVN) results in increased food intake and motivation for energy-dense foods. Here, we continue our focus on NMUR2 in the PVN, but in relation to the incubation effect on craving for high-fat food. We employed a model for incubation of craving by having rats abstain from high-fat foods for 30 days before undergoing intake of fatty food on fixed ratio and progressive ratio schedules of reinforcement, and then assess their response to reactivity to cues. Using this model, we compared the feeding behaviors of rats that underwent an mRNA knockdown of the NMUR2 in the PVN to controls after both underwent a 30-day abstinence from high-fat foods. Our results show knockdown of NMUR2 in the PVN blocks the incubation of feeding behavior for food-related cues and high-fat foods. [ABSTRACT FROM AUTHOR]

Resilience and vulnerability to neuropsychiatric disorders are linked to molecular changes underlying excitability that are still poorly understood. Here, we identify glycogen-synthase kinase 3β (GSK3β) and voltage-gated Na+ channel Nav1.6 as regulators of neuroplasticity induced by environmentally enriched (EC) or isolated (IC) conditions-models for resilience and vulnerability. Transcriptomic studies in the nucleus accumbens from EC and IC rats predicted low levels of GSK3β and SCN8A mRNA as a protective phenotype associated with reduced excitability in medium spiny neurons (MSNs). In vivo genetic manipulations demonstrate that GSK3β and Nav1.6 are molecular determinants of MSN excitability and that silencing of GSK3β prevents maladaptive plasticity of IC MSNs. In vitro studies reveal direct interaction of GSK3β with Nav1.6 and phosphorylation at Nav1.6T1936 by GSK3β. A GSK3β-Nav1.6T1936 competing peptide reduces MSNs excitability in IC, but not EC rats. These results identify GSK3β regulation of Nav1.6 as a biosignature ofMSNs maladaptive plasticity. [ABSTRACT FROM AUTHOR]

ABSTRACT The serotonin 5-HT2C receptor has shown promise in vivo as a pharmacotherapeutic target for alcoholism. For example, recently, a novel 4-phenyl-2- N, N-dimethylaminotetralin (PAT) drug candidate, that demonstrates 5-HT2C receptor agonist activity together with 5-HT2A/2B receptor inverse agonist activity, was shown to reduce operant responding for ethanol after peripheral administration to rats. Previous studies have shown that the 5-HT2C receptor is found throughout the mesoaccumbens pathway and that 5-HT2C receptor agonism causes activation of ventral tegmental area (VTA) GABA neurons. It is unknown what effect 5-HT2C receptor modulation has on GABA release in the nucleus accumbens core (NAcc). To this end, microdialysis coupled to capillary electrophoresis with laser-induced fluorescence was used to quantify extracellular neurotransmitter concentrations in the NAcc under basal and after potassium stimulation conditions, in response to PAT analogs and other 5-HT2C receptor modulators administered by reverse dialysis to rats. 5-HT2C receptor agonists specifically attenuated stimulated GABA release in the NAcc while 5-HT2C antagonists or inverse agonists had no effect. Agents with activity at 5-HT2A receptors had no effect on GABA release. Thus, in contrast to results reported for the VTA, current results suggest 5-HT2C receptor agonists decrease stimulated GABA release in the NAcc, and provide a possible mechanism of action for 5HT2C-mediated negative modulation of ethanol self-administration. Synapse 69:78-85, 2015. © 2014 Wiley Periodicals, Inc. [ABSTRACT FROM AUTHOR]

Binge-eating disorder (BED) is the most common eating disorder, characterized by rapid, recurrent overconsumption of highly palatable food in a short time frame. BED shares an overlapping behavioral phenotype with obesity, which is also linked to the overconsumption of highly palatable foods. The reinforcing properties of highly palatable foods are mediated by the nucleus accumbens (NAc) and the ventral tegmental area (VTA), which have been implicated in the overconsumption behavior observed in BED and obesity. A potential regulator of binge-type eating behavior is the G protein-coupled receptor neuromedin U receptor 2 (NMUR2). Previous research demonstrated that NMUR2 knockdown potentiates binge-type consumption of high-fat food. We correlated binge-type consumption across a spectrum of fat and carbohydrate mixtures with synaptosomal NMUR2 protein expression in the NAc and VTA of rats. Synaptosomal NMUR2 protein in the NAc demonstrated a strong positive correlation with binge intake of a "lower"-fat (higher carbohydrate) mixture, whereas synaptosomal NMUR2 protein in the VTA demonstrated a strong negative correlation with binge intake of an "extreme" high-fat (0% carbohydrate) mixture. Taken together, these data suggest that NMUR2 may differentially regulate binge-type eating within the NAc and the VTA. [ABSTRACT FROM AUTHOR]